Role of hormones in the regulation of RACK1 expression as a signaling checkpoint in immunosenescence

Immunosenescence defines the decline in immune function that occurs with aging.
This has been associated, at least in part, with defective cellular signaling via
protein kinase C (PKC) signal transduction pathways. Our data suggest reduced PKC
activation and consequently reduced response to lipopolysaccharide (LPS)
stimulation and cytokine release. The lack of PKC activation seems to be
dependent on the reduced expression of the receptor for activated C kinase 1
(RACK1), a scaffolding protein involved in multiple signal transduction cascades.
The defective expression of RACK1 may be dependent on age-related alteration of
the balance between the adrenal hormones cortisol and dehydroepiandrosterone
(DHEA). DHEA levels reduce with aging, while cortisol levels remain substantially
unchanged, resulting in an overall increase in the cortisol:DHEA ratio. These
hormonal changes are significant in the context of RACK1 expression and signaling
function because DHEA administration in vivo and in vitro can restore the levels
of RACK1 and the function of the PKC signaling cascade in aged animals and in
human cells. In contrast, there is evidence that cortisol can act as a negative
transcriptional regulator of RACK1 expression. The rack1 gene promoter contains a
glucocorticoid responsive element that is also involved in androgen signaling.
Furthermore DHEA may have an indirect influence on the post-transcriptional
regulation of the functions of the glucocorticoid receptor. In this review, we
will examine the role of the hormonal regulation of rack1 gene transcriptional
regulation and the consequences on signaling and function in immune cells and
immunosenescence.